Central melanin-concentrating hormone neural pathways and obesity

中枢黑色素浓缩激素神经通路与肥胖

• 批准号: 10190403
• 负责人: Emily Elizabeth Noble
• 金额: $ 10.65万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190403
• 关键词: Acute; Address; Adenylate Cyclase; Adult; Affect; Anatomy; Animals; Automobile Driving; Behavioral; Binge Eating; Body Weight; Body Weight decreased; Brain; COVID-19; Cardiovascular Diseases; Cilia; Data; Development; Diabetes Mellitus; Diet; Eating; Eating Behavior; Energy Intake; Energy Metabolism; Equation; Fatty acid glycerol esters; Feeding behaviors; Female; Food; Food Energy; Future; Gene Expression; Genetic; Goals; Hippocampus (Brain); Home; Homeostasis; Hyperphagia; Hypothalamic structure; Impairment; Impulsivity; In Vitro; Injections; Intake; Investigation; Lateral Hypothalamic Area; Length; Leptin; MCHR1 gene; Malignant Neoplasms; Mediating; Medical; Mentored Research Scientist Development Award; Methodology; Molecular; Morbid Obesity; Neural Pathways; Neurologic; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Obesity Epidemic; Output; Palate; Pathway interactions; Pharmacotherapy; Play; Population; Predisposition; Process; Public Health; Publishing; RNA Interference; Rattus; Reducing diet; Risk Factors; Role; Satiation; Sex Differences; Signal Transduction; Signaling Protein; Site; System; Testing; Unconscious State; Virus; Weight Gain; Work; base; design; designer receptors exclusively activated by designer drugs; diet-induced obesity; effectiveness evaluation; energy balance; experimental study; feeding; gamma-Aminobutyric Acid; hormonal signals; in vivo; knock-down; loss of function; male; melanin-concentrating hormone; melanin-concentrating hormone receptor; neurobiological mechanism; novel; novel coronavirus; obesity prevention; obesity treatment; optogenetics; relating to nervous system; sex; sexual dimorphism; sugar; zona incerta

Project Summary/Abstract Despite considerable efforts to address and reverse the obesity epidemic, obesity remains highly prevalent in the U.S. The brain plays an important role in regulating body weight, both through modulating energy expenditure and driving feeding behavior, and thus understanding how the brain regulates energy balance is critical for developing effective obesity treatments. Melanin-concentrating hormone (MCH) is a neuropeptide that acts in the brain to promote weight gain by increasing food intake and reducing energy expenditure. Due to its dual actions on both aspects of the energy balance equation, the MCH system is a promising target for obesity pharmacotherapies. Currently, the mechanisms and neural sites of action by which MCH modulates energy balance are largely unknown. The overarching goal of this proposal is to identify neural sites of action and mechanisms by which MCH promotes hyperphagia and susceptibility to diet induced obesity. Specific Aim 1A and 1B utilizes two novel virogenetic RNA interference approaches to promote a loss of function to the MCH system in the paraventricular hypothalamus (PVH). Animals are then challenged with a palatable high fat, high sugar, Western cafeteria diet in order to determine whether the PVH MCH system plays a role in the development of diet induced obesity. Experiments are performed in male and female rats, with the potential for further investigation into sex differences should sexually dimorphic effects be observed. Specific Aim 1C investigates a novel molecular mechanism by which MCH may alter feeding effects, namely by modulating the length of neuronal primary cilia and/or gene expression of the ciliary signaling protein adenylyl cyclase 3 (AC3). Specific Aim 2A investigates the function of zona incerta (ZI) MCH neurons, a population whose behavioral function has not been studied in isolation with regards to feeding behavior. Based on our unpublished preliminary data and recent published work, we propose that ZI MCH neurons increase binge-eating behavior. We will examine this question using our MCH neuron-specific chemogenetic DREADDs approach. We further plan to determine the downstream anatomical outputs of ZI MCH neurons, which will enable us to employ our dual virus chemogenetic approach in future studies in order to better understand the function of the multi-order circuitry of this unique population of MCH neurons. These experiments build on the experiments from the applicant's K01 proposal and are specifically designed to produce necessary data for the applicants R01 application. The studies outlined herein will additionally contribute significantly to understanding the role of the MCH signaling in regulating energy balance, which is an important step toward effectively developing obesity pharmacotherapies based on this system.

项目摘要/摘要 尽管努力解决和扭转肥胖症的流行，但肥胖仍然很高 在美国，大脑在调节体重方面起着重要作用，既通过调节 能源消耗和驱动喂养行为，从而了解大脑如何调节能量 平衡对于发展有效的肥胖治疗至关重要。黑色素浓缩激素（MCH）是 通过增加食物摄入并减少能量来促进体重增加的神经肽 支出。由于其对能量平衡方程的两个方面的双重动作，MCH系统是一个 肥胖药物治疗的有希望的靶标。目前，机制和神经作用部位 MCH调节能量平衡在很大程度上未知。该提议的总体目标是确定 神经作用和机制的神经部位促进了脾气和饮食的易感性 诱发肥胖。特定的目标1a和1b利用两种新型的病毒RNA干扰方法来促进 脊髓脊髓下丘脑（PVH）中MCH系统的功能丧失。然后挑战动物 使用可口的高脂，高糖，西方自助餐厅饮食，以确定PVH MCH是否是否 系统在饮食诱导的肥胖症的发展中起作用。实验是在男性和女性中进行的 大鼠，有可能进一步研究性别差异 观察到。特定的目标1C研究了一种新型分子机制，通过该机制，MCH可以改变进食效果， 也就是通过调节纤毛信号传导的神经元原发性纤毛的长度和/或基因表达 蛋白腺苷酸环化酶3（AC3）。特定的目标2a研究Zona incerta（Zi）MCH神经元的功能，A 在喂养行为方面尚未孤立研究其行为功能的人群。基于 在我们未发表的初步数据和最近发表的工作中，我们建议Z​​i MCH神经元增加 暴饮暴食的行为。我们将使用我们的MCH神经元特异性化学遗传学恐惧症来检查这个问题 方法。我们进一步计划确定ZI MCH神经元的下游解剖输出，该输出将 使我们能够在未来的研究中利用双重病毒化学发生方法，以便更好地了解 这种独特的MCH神经元种群的多阶电路的功能。这些实验基于 申请人的K01提案的实验，专门设计用于生成必要的数据 适用于申请人R01申请。本文概述的研究将对 了解MCH信号在调节能量平衡中的作用，这是迈向的重要一步 根据该系统有效开发肥胖药物疗法。